The common and typical induction of osteolytic bone disease in multiple myeloma (MM) led to the notion that bone disease is both a consequence and a necessity of MM progression and metastasis. Our reported and preliminary data suggest that osteoclasts support myeloma cell survival and metastasis through production of certain serine proteases known as dipeptidyl peptidase-IV activity and/or structure homolog (DASH) proteins and that inhibiting activity of osteoclasts or DASH proteases suppresses growth of medullary MM. Conversely, we found that osteoblasts reduce growth of myeloma cells through production of certain small leucine-rich proteoglycans and that increased osteoblast activity in myelomatous bones (from treating with osteoblast-activating agents [parathyroid hormone or anti-DKKI] or with cytotherapy [osteoprogenitor cells]) increases bone formation, creating an inhospitable microenvironment that attenuates MM progression in vivo. Based on these findings, we hypothesize that the microenvironment in existing focal lesions is a critical determinant of long-term survival and dissemination of myeloma cells; therefore, simultaneously inhibiting osteoclast activity and stimulating bone formation is critical for sustaining a patient's response to treatment and for preventing metastasis. In Specific Aim 1, we will determine whether increased bone formation by bone-anabolic agents (e.g., PTH, anti-DKKI), with or without exogenous osteoblast precursors, will sustain remission induced by clinical agents (e.g., melphalan, dexamethasone, bortezomib, lenalidomide), and/or prevent tumor metastasis upon relapse. We will also investigate molecular mechanisms associated with these effects. In Specific Aim 2, we will determine whether osteoclast-produced DASH proteases contribute to MM-induced bone disease, support survival of MM in osteolytic lesions, and stimulate metastasis directly by signaling through caveolae and indirectly through reduced retention of myeloma cells by inactivating the central chemokine SDF-1. In Specific Aim 3, we will determine whether combining treatments to increase activity of osteoblasts and inhibit activity of DASH proteases has superior effects on controlling MM growth and dissemination and on preventing relapse than either individual therapeutic approach. Through interactions with all projects and cores, using our SCID-hu model and coculture systems with primary samples and myeloma cell lines, we will unravel antitumor and antimetastatic effects of factors associated with bone anabolism, as well as molecular mechanisms of DASH proteases in MM using gain-and-loss approaches, specific inhibitors, and recombinant proteins.